Inhibition of the biosynthesis of complex N‐glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi α‐mannosidase II (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co‐inhibition of lysosomal α‐mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N‐substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 α‐mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (K_i=50–76 μm, as determined by enzyme assays) with a significant selectivity index of IC₅₀(LManII)/IC₅₀(GMIIb) >100. These compounds also showed inhibitory activities in in vitro assays with cancer cell lines (leukemia, IC₅₀=92–200 μm) and low cytotoxic activities in normal fibroblast cell lines (IC₅₀>200 μm). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoiα1,2‐mannosidase. An appropriate stereo configuration of hydroxymethyl and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity for the active site of a target α‐mannosidase.

中文翻译：

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多羟基吡咯烷的 N-苄基取代：高尔基体 α-甘露糖苷酶 II 选择性抑制剂的途径

抑制高尔基体中复杂 N-聚糖的生物合成会影响肿瘤生长和转移的进展。高尔基体 α-甘露糖苷酶 II (GMII) 已成为具有抗癌活性的药物的治疗靶点。将 GMII 药物成功应用于医学治疗的一项关键任务是减少它们对溶酶体 α-甘露糖苷酶 (LMan) 的不必要的共抑制，这是所有已知强效 GMII 抑制剂的弱点。合成了一系列新型 N 取代的多羟基吡咯烷，并用来自黑腹果蝇的模型化 GH38 α-甘露糖苷酶（GMIIb 和 LManII）进行了测试。最有效的结构抑制 GMIIb ( K _i =50–76 μ m，由酶测定确定)，具有显着的 IC _{50选择性指数}(LManII)/IC ₅₀ (GMIIb) >100。这些化合物还在癌细胞系的体外试验中显示出抑制活性（白血病，IC ₅₀ =92–200 μ m），在正常成纤维细胞系中显示出低细胞毒活性（IC ₅₀ >200 μ m）。此外，它们对 GH47 Aspergillus saitoi α1,2-甘露糖苷酶没有表现出任何显着的抑制活性。抑制剂吡咯烷环上羟甲基和苄基官能团的适当立体构型可能会导致抑制剂对目标α-甘露糖苷酶的活性位点具有所需的选择性。